This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Influenza, a highly communicable acute respiratory disease, is one of the major infectious disease threats to the human population. Some of the challenges in developing an effective vaccine for influenza occur because influenza viruses exhibit change in genetic structure each season. None of the current vaccines offer protection in a way that accounts for this genetic change. VaxInnate has developed a cross-protective influenza A vaccine, VAX102, which is based on a recombinant protein expressed in E. coli. We have found that 0.3 g and 1.0 g are safe and immunogenic doses when given intramuscularly (IM) and we have found that higher doses such as 10 g are associated with unacceptable symptoms of cytokine release. The subcutaneous tissues are less vascular than muscle and may lead to slower systemic uptake of vaccine. We will assess the safety, reactogenicity, and tolerability of the VAX102 vaccine delivered IM, SC, and ID at dose levels 0.3 [unreadable]g, 1 [unreadable]g, and 2[unreadable]g in a prime-boost dosing regimen, in healthy adults 18- 49 years of age. Subjects will be asked to keep a diary of local reactions (i.e., erythema, induration) and systemic symptoms such as pain and fatigue. Subjects will be followed frequently during the one month post each dose of study agent, and will be contacted by phone at 6 months following the first vaccine dose. Novel influenza vaccines and new approaches to production are critical to both national and international health.